PROJECT SUMMARY/ABSTRACT This proposal will investigate how Sufu regulates neural stem cell behavior and its implications in tumorigenesis. In particular, the role of Suppressor of Fused (Sufu), a tumor suppressor gene and a critical negative regulator of Shh signaling, will be examined in the postnatal neural stem cell (NSC) population. Preliminary studies show that conditional deletion of Sufu results in abnormal proliferation of NSC in the subventricular zone (SVZ) of the embryonic and postnatal forebrain. Also, experiments also showed that Sufu interacts with the tumor suppressor, p53. These findings indicate that Sufu plays an important role in regulating cell number in the progenitor zones. The aims below will investigate how Sufu regulates p53 to influence NSC behavior and determine how this might contribute to the formation of tumors in the forebrain. The questions that will be addressed in this proposal are as follows: Aim 1: Does Sufu regulate the proliferation of specific stem cell lineages within the postnatal SVZ? Aim 2: Does Sufu directly regulate p53 activity in the embryonic and postnatal SVZ? Aim 3: In the absence of p53, will loss of Sufu in NSCs lead to tumor formation? The applicant, Odessa Yabut, Ph.D., is a Postdoctoral Scholar who plans to develop an independent research career focusing on NSC and tumor formation. Dr. Yabut will take advantage of the opportunities offered by the Career Development Award to deepen her knowledge of NSC biology in the postnatal brain and begin in-depth studies on brain tumors at UCSF, a premier research institute devoted to the success of its postdoctoral scholars. Dr. Yabut will also learn a set of new skills, techniques, and collaborative opportunities. Dr. Yabut will conduct these studies under the mentorship of Samuel Pleasure, M.D., Ph.D., who is an established scientist in forebrain development. Anders Persson, Ph.D., an expert in brain tumors, will act as a co-mentor. She will also have an advisory committee composed of David Rowitch, M.D., Ph.D. and Daniel Lim, M.D., Ph.D, who are experts in NSC development and tumorigenesis. With Dr. Pleasure and her advisory committee, Dr. Yabut will enhance her knowledge on the mechanisms governing NSC development and brain tumors, hone her critical thinking skills, and help in her transition as an independent academic scientist.